6-51830849-A-T

Variant names:

• chr6-51830849-A-T
• rs1571084
• NM_138694.4:c.8302+12T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.8302+12T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,609,244 control chromosomes in the GnomAD database, including 143,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16090 hom., cov: 32)
  • Exomes 𝑓: 0.41 (127005 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.317

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-51830849-A-T is Benign according to our data. Variant chr6-51830849-A-T is described in ClinVar as [Benign]. Clinvar id is 96429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51830849-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.8302+12T>A		intron_variant	Intron 52 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8302+12T>A		intron_variant	Intron 52 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.8302+12T>A		intron_variant	Intron 52 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67445 AN: 151822 Hom.: 16065 Cov.: 32

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.0830

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.479

GnomAD3 exomes AF: 0.375 AC: 94101 AN: 250980 Hom.: 19966 AF XY: 0.378 AC XY: 51247 AN XY: 135654

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.0823

Gnomad SAS exome AF: 0.308

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.409 AC: 596261 AN: 1457304 Hom.: 127005 Cov.: 31 AF XY: 0.407 AC XY: 294944 AN XY: 725232

Gnomad4 AFR exome AF: 0.600

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.553

Gnomad4 EAS exome AF: 0.0849

Gnomad4 SAS exome AF: 0.312

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.444 AC: 67518 AN: 151940 Hom.: 16090 Cov.: 32 AF XY: 0.434 AC XY: 32257 AN XY: 74248

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.0829

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.427

Gnomad4 OTH AF: 0.477

Alfa AF: 0.443 Hom.: 2885

Bravo AF: 0.456

Asia WGS AF: 0.259 AC: 901 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 4 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.8302+12T>A, p.? variant was identified in 38.61% of 46763 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.89
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1571084; hg19: chr6-51695647; COSMIC: COSV61861095;